Acoustic information necessary for localizing sounds and for understanding speech is carried in the timing of firing of neurons. In human patients with auditory neuropathy the loss of temporal resolution in auditory nerve fibers leads to reduced auditory brainstem responses (ABRs), the inability to use interaural timing cues for lateralizing sounds, elevated gap detection thresholds and to difficulty in understanding speech. Our research will elucidate mechanisms that enable mammals to use timing information for localizing and understanding the meaning of sounds and how hearing impairment perturbs them. Timing information is carried from the cochlea, through two of the three parallel ascending pathways from the ventral cochlear nucleus (VCN), and through an additional synaptic stage in brain stem auditory nuclei before reaching the inferior colliculus where timing information is lost or encoded differently. Hyperpolarization-activated mixed cation (gh) and low-voltage- activated potassium (gKL) conductances are thought to be essential for the ability of auditory neurons in the brain stem to encode timing information. Neurons that encode timing in the cochlear nuclei of mice that lack the HCN1 subunit have reductions not only in gh but also in gKL. Mice with these deficits hear but the reduction and mistiming of early waves of the ABR indicates that the encoding of timing in the brain stem is altered. By perturbing magnitudes of gh and gKL outside the normal range in mutant mice, we will learn how the expression of the corresponding ion channels is regulated and how gh and gKL contribute to detecting gaps, a task that is associated with understanding the meaning of sounds. We propose to use these mutant mice 1) to understand how alterations in biophysical properties of neurons in the VCN affect summation of depolarizing currents, 2) to determine whether the expression of Ih regulates the expression of IKLin octopus and bushy cells 3) to determine how the biophysical properties of neurons affect pre- and postsynaptic functions in the VCN, and 4) to test how biophysical properties of neurons in the VCN correlate with auditory brainstem evoked potentials (ABRs) and with behavioral tests of gap detection thresholds. These aims will allow us to understand how perturbations in specific conductances affect properties of neurons that encode timing and how these perturbations affect the ability to hear. PUBLIC HEALTH RELEVANCE: We propose to examine how the expression of conductances necessary for the encoding of acoustic information in the timing of firing is regulated and how a reduction in these conductances affects hearing. Loss of the ability to encode precisely timed signals in auditory neuropathy causes human patients to lose the ability to understand speech. By perturbing genetically the expression of conductances in mice that sharpen electrical signaling, we will determine how those conductances are regulated and how they contribute to detecting gaps in sounds. These experiments will elucidate how pathways through the brain stem carry information necessary for understanding speech.